A major signal inducing regenerative lung growth in adult dogs after pneumonectomy (PNX) is thought to be alveolar stretch due to expansion of the remaining lung. We found that preventing lung expansion after right PNX by an inflated silicone prosthesis customized to the shape of the normal right lung does not completely prevent regenerative alveolar growth, suggesting that other stimuli such as increased blood flow through the remaining lung, are also important. Our objective is to characterize the time course and magnitude of structural, cellular and physiologic responses induced by lung expansion and non-expansion related signals for regenerative lung growth in fully mature dogs after PNX when these signals are temporally isolated from the acute surgical trauma, stress and tissue repair. Lung expansion after right PNX will be prevented by an inflated prosthesis for 2 to 6 mo. Then the prosthesis is deflated allowing lung expansion. Physiologic compensation will be assessed serially before and after deflation by a rebreathing method and high resolution CT scan in separate groups of animals. Physiological measurements include pressure-volume relationships, maximal o2 uptake, lung diffusing capacity (DLco) and its components membrane diffusing capacity (DMco) and capillary blood volume (Vc), as well as relationships of DLco, DMco and Vc to pulmonary blood flow during exercise. At 2 to 10 mo. after prosthesis deflation, lung tissue is harvested for detailed structural analysis by morphometry, and for studying the localization and expressions of epidermal growth factor (EGF) and its receptor (EGFR) by immunohistochemical, immunogold labeling, immunoblot, immunoprecipitation and RNA blot. Time points selected will allow comparison of short-term or long-term growth responses to lung expansion without the confounding effects of surgical trauma and inflammation, and to determine differential effects of early or delayed application of mechanical alveolar stretch after PNX on growth and compensation. Correlations between physiological compensation, growth factor expression and structural growth will also be defined. This proposal addresses fundamental issues regarding the mechanisms and signals that mediate lung growth in fully mature animals. This is the first model to systematically isolate and dissect the major putative stimuli of lung growth in vivo. Results have broad scientific importance to understanding growth-regulating mechanisms and will advance our long-range goal, which is to explore therapeutic approaches that can augment regenerative lung growth in patients with chronic lung disease.